Topoisomerase Inhibitors

Topoisomerase inhibitors are compounds that block the activity of an enzyme called topoisomerase 1 (Top1) which is primarily involved in DNA structural changes during cell division. Topoisomerase inhibitors are already being used as anticancer medications and may have additional uses in treating Angelman syndrome.

What are topoisomerases?

Topoisomerases such as Top1 are enzymes that help in changing the structure of DNA during processes such as DNA replication where the entire genetic material inside cells is duplicated before the cell divides and gives rise to two identical daughter cells. Targeting topoisomerases with inhibitors, therefore, prevents the cell from dividing and is one of the approaches used in anticancer therapy.

How do topoisomerase inhibitors work for Angelman syndrome?

Angelman syndrome is a neurological genetic disorder caused by mutations in the UBE3A gene and is characterized by delayed physical and mental development.

Everyone has two copies of every gene — one copy from each parent. In certain regions of the brain, only the maternal copy of the UBE3A gene is active while the paternal copy is silenced. A healthy maternal copy of UBE3A is therefore essential for proper neurologic function. In Angelman syndrome, the maternal copy of the UBE3A gene is mutated, resulting in serious physical and mental disabilities.

For the cell to make proteins, genes first need to get transcribed into a temporary molecule called RNA. The instructions from this RNA later get translated into protein. Inhibition of Top1 by topoisomerase inhibitors prevents genes from being transcribed into RNA, thereby restricting gene function.

Research has shown that topoisomerase inhibitors can unsilence the paternal copy of the UBE3A gene in the brain. They do this by preventing the production of the RNA that silences paternal UBE3A. Thus, paternal UBE3A can then perform the functions of the maternal copy, which results in reducing the severity of Angelman syndrome symptoms.

Currently, topoisomerase inhibitors such as topotecan and indotecan are being studied in mouse models of Angelman syndrome.


A study found 16 topoisomerase inhibitors to be effective in unsilencing the paternal copy of UBE3A in nerve cells obtained from mice and grown in the laboratory. Of these, topotecan was found to be effective in promoting UBE3A gene activity at low concentrations, with its effect lasting for about 12 weeks after administration. However, the effect of topotecan in humans with Angelman’s syndrome is not yet known.


Indotecan is a topoisomerase inhibitor that works similarly to topotecan. Researchers chose indotecan from about 13 topoisomerase inhibitors that could unsilence the UBE3A gene in mouse nerve cells grown in the laboratory.

The study found indotecan to be more efficient than topotecan and less likely to be pumped out of the brain due to its chemical structure. Lower levels of the treatment may therefore be sufficient, but its bioavailability relative to that of topotecan still needs to be properly determined, the researchers said. The safety of the compound also needs to be carefully evaluated in preclinical studies before it can be tested in clinical trials.


Last updated: Sept. 10, 2019


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